SWATH-MS for prospective identification of protein blood biomarkers of rtPA-associated intracranial hemorrhage in acute ischemic stroke: a pilot study.

Intravenous recombinant tissue plasminogen activator (rtPA) is, besides mechanical thrombectomy, the highest class evidence based reperfusion treatment of acute ischemic stroke (AIS). The biggest concern of the therapy is symptomatic intracranial hemorrhage (sICH), which occurs in 3-7% of all treated patients, and is associated with worse functional outcome. Finding a method of the powerful identification of patients at highest risk of sICH, in order to increase the percentage of stroke patients safely treated with rtPA, is one of the most important challenges in stroke research. To address this problem, we designed a complex project to identify blood, neuroimaging, and clinical biomarkers combined for prospective assessment of the risk of rtPA-associated ICH. In this paper we present results of blood proteomic and peptide analysis of pilot 41 AIS patients before rtPA administration (the test ICH group, n = 9 or the controls, without ICH, n = 32). We demonstrated that pre-treatment blood profiles of 15 proteins differ depending on whether the patients develop rtPA-associated ICH or not. SWATH-MS quantification of serum or plasma proteins might allow for robust selection of blood biomarkers to increase the prospective assessment of rtPA-associated ICH over that based solely on clinical and neuroimaging characteristics.

New Remote Cerebral Microbleeds on T2*-Weighted Echo Planar MRI After Intravenous Thrombolysis for Acute Ischemic Stroke.

BACKGROUND: The main and well-defined complication of intravenous administration of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is symptomatic intracranial hemorrhage (sICH). However, rtPA might also be connected with the formation of cerebral microbleeds (CMBs), located remotely from the ischemic lesions, that may remain clinically silent. This association might be important because the load of CMBs has been associated with cognitive impairment. We investigated whether administration of rtPA in AIS results in the appearance of new CMBs and if the initial load of CMBs is associated with hemorrhagic transformation. METHODS: A total of fifty-nine consecutive patients with AIS treated with rtPA underwent MRI including T2*-weighted Echo Planar Imaging (T2*-EPI) shortly before and 7-9 days after rtPA administration. We calculated the load of new CMBs located outside the MR diffusion restriction area in the follow-up imaging and assessed hemorrhagic transformation with ECASS-II scoring. RESULTS: A total of forty-nine patients were included for the final analysis. On initial T2*-EPI-GRE, 37 baseline microbleeds (CMBs) were observed in 14 patients (28.6%). On follow-up T2*-EPI-GRE amount of CMBs increased to a total number of 103. New CMBs were found in 5 (14.3%) of 35 patients without and in 9 (64.3%) of 14 with any baseline CMBs. Multiple logistic regression analysis indicated that presence of baseline CMBs (risk ratio [RR] 5.95, 95% CI 2.69-13.20, p < 0.001) and lower platelets level (risk ratio [RR] 0.992, 95% CI 0.986-0.998, p = 0.007) were independently associated with new CMBs. The baseline load of CMBs was not associated with the risk of hemorrhagic transformation. CONCLUSION: In this study, new CMBs were found in nearly 30% of patients with AIS on the 7-9 days after rtPA treatment. Baseline CMBs correlated with a higher risk of new CMBs appearing after the rtPA treatment, independently of other factors. At the same time, in our sample, baseline CMBs did not correlate with an increased risk of hemorrhagic transformation. Since the associations between the CMBs load and cognitive impairment have already been proved, further studies are warranted to investigate possible associations between the thrombolytic treatment of patients with AIS, mainly those with baseline CMBs, and the risk of earlier cognitive decline.